This invention is generally in the area of drug delivery systems and is particularly related to methods of reversible microencapsulation of drugs by certain derivatives of 2,5-diketopiperazine, modified diketopiperazine microparticles, and use thereof.
Delivery of drugs has been a major problem for many years, particularly when the compound to be delivered is unstable under the conditions encountered in the gastro-intestinal tract when administered orally to a subject, prior to reaching its targeted location. For example, it is preferable in many cases to administer drugs orally, especially in terms of ease of administration, patient compliance, and decreased cost. However, many compounds are ineffective or exhibit low or variable potency when administered orally. Presumably this is because the drugs are unstable to conditions in the digestive tract or because they are inefficiently absorbed.
A variety of enteric coatings have been used to encapsulate and protect the drug prior to reaching the small intestine. In some cases these coatings are effective. However, there are drugs that are unstable to the conditions present in the small intestine and therefore must be administered in much higher dosages if the drug is to be released in the small intestine so that an effective amount is absorbed by the bloodstream. In these cases, it is necessary to have a mechanism whereby the coating is not only stable to the conditions present in the digestive tract, as well as to the conditions under which it is stored prior to administration to the patient, but which allows the encapsulated drug to pass into the bloodstream.
A broad range of delivery systems, including microparticles and microspheres, that are small enough to be administered intravenously, have been developed. It is desirable in some cases for these to be insoluble in the blood, as well as under the conditions under which the delivery system is stored prior to administration to the patient. Release of the encapsulated drug can occur following uptake by phagocytic cells. Controlled release of drug can also occur by diffusion out of the slowly degrading microparticles.
Other factors in drug delivery system design include the requirements that the system must be non-toxic, non-reactive with the drug to be delivered, not too expensive or difficult to manufacture, formed of readily available components, and consistent with respect to final composition and physical characteristics, including stability and release rate. The system must also be formed of materials that are easily removed by normal metabolic processes.
U.S. Ser. No. 07/849,186 filed Mar. 11, 1992, describes a drug delivery system based on the formation of diketopiperazine microparticles from diketopiperazine derivatives containing a single six membered ring diketopiperazine, which are stable at low pH and disintegrate at the pH present in the blood or small intestine. The drug to be delivered is encapsulated within the diketopiperazine microparticles by dissolving the diketopiperazine in a basic solution, adding the drug in solution or suspension, then solidifying the structure by adding acid.
However, it would be preferable to have other methods for forming diketopiperazine microparticles that allow for encapsulation of other materials, especially those which are not stable or soluble under the conditions disclosed in U.S. Ser. No. 07/849,186 filed Mar. 11, 1992. It would also be preferable to have microparticles made from modified diketopiperazine derivatives such that the microparticles disintegrate under a variety of conditions. It would further be preferable to be able to target the microparticles to uptake by particular cells, and conditions where release occurs only within or at the targeted cells.
It is therefore an object of the present invention to provide improved methods for making a system for drug delivery which, by intentional modifications to its structure, can be made to be stable or unstable in a variety of physiological conditions, and methods for use thereof.
It is another object of the present invention to provide methods for making a system which is self-assembling, can be manufactured economically from currently available reagents, and can be targeted to specific cells.
It is still another object of the present invention to provide a process for encapsulation of insoluble, hydrophobic, or labile drugs.